Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
J Cardiovasc Pharmacol. 2017 Dec;70(6):356-361. doi: 10.1097/FJC.0000000000000529.
Clopidogrel is one of the most frequently prescribed drugs worldwide; however, the presence of clopidogrel resistance and high susceptibility to genetic variations and drug interactions are facilitating the development of other antiplatelet drugs. To overcome clopidogrel resistance, several promising clopidogrel analogues have been developed in China, such as vicagrel (and its deuterated analogues), PLD-301, and W1. These novel chemical analogues are all characterized by much faster and more efficient bioconversion to clopidogrel thiolactone (or 2-oxo-clopidogrel, the precursor of clopidogrel active metabolite) in the intestine than clopidogrel itself through bypassing the first-step P450-mediated oxidation of clopidogrel in the liver. Of them, metabolic conversion of vicagrel and PLD-301 to 2-oxo-clopidogrel is catalyzed by intestinal carboxylesterase 2 and alkaline phosphatase, respectively. In this review article, we summarized all evidence on highly efficient bioconversion to their shared precursor of clopidogrel active metabolite and the mechanisms underlying such a pronounced improvement. These drugs in the pipeline would be promising antiplatelet drugs that could be superior to clopidogrel in future patient care.
氯吡格雷是全球应用最广泛的药物之一；然而，氯吡格雷抵抗的存在以及对遗传变异和药物相互作用的高度敏感性，促使其他抗血小板药物的发展。为了克服氯吡格雷抵抗，中国已经开发了几种有前途的氯吡格雷类似物，如维卡格雷（及其氘代类似物）、PLD-301 和 W1。这些新型化学类似物的特点是在肠道中通过绕过肝脏中氯吡格雷的第一步 P450 介导的氧化，比氯吡格雷本身更快、更有效地生物转化为氯吡格雷硫醇内酯（或 2-氧代-氯吡格雷，氯吡格雷活性代谢物的前体）。其中，维卡格雷和 PLD-301 转化为 2-氧代-氯吡格雷的代谢转化分别由肠道羧酸酯酶 2 和碱性磷酸酶催化。在这篇综述文章中，我们总结了所有关于高效生物转化为其共同前体氯吡格雷活性代谢物的证据，以及这种显著改善的机制。这些在研药物将是有前途的抗血小板药物，在未来的患者治疗中可能优于氯吡格雷。
